EP1747190B1 - Process for the preparation of valsartan and precursors thereof - Google Patents
Process for the preparation of valsartan and precursors thereof Download PDFInfo
- Publication number
- EP1747190B1 EP1747190B1 EP05733764A EP05733764A EP1747190B1 EP 1747190 B1 EP1747190 B1 EP 1747190B1 EP 05733764 A EP05733764 A EP 05733764A EP 05733764 A EP05733764 A EP 05733764A EP 1747190 B1 EP1747190 B1 EP 1747190B1
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- European Patent Office
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- 239000004072 C09CA03 - Valsartan Substances 0.000 title claims abstract description 37
- 229960004699 valsartan Drugs 0.000 title claims abstract description 36
- 238000000034 method Methods 0.000 title claims description 37
- 230000008569 process Effects 0.000 title claims description 37
- SJSNUMAYCRRIOM-QFIPXVFZSA-N valsartan Chemical compound C1=CC(CN(C(=O)CCCC)[C@@H](C(C)C)C(O)=O)=CC=C1C1=CC=CC=C1C1=NN=N[N]1 SJSNUMAYCRRIOM-QFIPXVFZSA-N 0.000 title abstract 3
- 239000002243 precursor Substances 0.000 title 1
- 230000015572 biosynthetic process Effects 0.000 claims abstract description 38
- 238000003786 synthesis reaction Methods 0.000 claims abstract description 35
- 238000004519 manufacturing process Methods 0.000 claims abstract description 24
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims abstract description 8
- 230000006181 N-acylation Effects 0.000 claims abstract description 7
- 150000001875 compounds Chemical class 0.000 claims description 56
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 35
- KZSNJWFQEVHDMF-BYPYZUCNSA-N L-valine Chemical compound CC(C)[C@H](N)C(O)=O KZSNJWFQEVHDMF-BYPYZUCNSA-N 0.000 claims description 34
- ACWBQPMHZXGDFX-QFIPXVFZSA-N valsartan Chemical compound C1=CC(CN(C(=O)CCCC)[C@@H](C(C)C)C(O)=O)=CC=C1C1=CC=CC=C1C1=NN=NN1 ACWBQPMHZXGDFX-QFIPXVFZSA-N 0.000 claims description 34
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 33
- 229960004295 valine Drugs 0.000 claims description 32
- 239000000203 mixture Substances 0.000 claims description 30
- 229910001868 water Inorganic materials 0.000 claims description 29
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 27
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 24
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 24
- 238000006243 chemical reaction Methods 0.000 claims description 24
- 150000007530 organic bases Chemical class 0.000 claims description 22
- 239000003960 organic solvent Substances 0.000 claims description 22
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 21
- 150000007529 inorganic bases Chemical class 0.000 claims description 17
- 239000002904 solvent Substances 0.000 claims description 16
- 150000003536 tetrazoles Chemical group 0.000 claims description 14
- 229910052799 carbon Inorganic materials 0.000 claims description 13
- FFUAGWLWBBFQJT-UHFFFAOYSA-N hexamethyldisilazane Chemical group C[Si](C)(C)N[Si](C)(C)C FFUAGWLWBBFQJT-UHFFFAOYSA-N 0.000 claims description 13
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 claims description 12
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 12
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 claims description 12
- 238000006073 displacement reaction Methods 0.000 claims description 11
- 229910052736 halogen Inorganic materials 0.000 claims description 11
- 150000002367 halogens Chemical class 0.000 claims description 11
- XSXHWVKGUXMUQE-UHFFFAOYSA-N osmium dioxide Inorganic materials O=[Os]=O XSXHWVKGUXMUQE-UHFFFAOYSA-N 0.000 claims description 11
- 125000006239 protecting group Chemical group 0.000 claims description 11
- 125000003944 tolyl group Chemical group 0.000 claims description 11
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 11
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 10
- GVRXWYFECKHTSJ-UHFFFAOYSA-N [2-(2h-tetrazol-5-yl)phenyl]boronic acid Chemical compound OB(O)C1=CC=CC=C1C1=NNN=N1 GVRXWYFECKHTSJ-UHFFFAOYSA-N 0.000 claims description 10
- 238000005859 coupling reaction Methods 0.000 claims description 10
- 230000007062 hydrolysis Effects 0.000 claims description 10
- 238000006460 hydrolysis reaction Methods 0.000 claims description 10
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 10
- 238000005580 one pot reaction Methods 0.000 claims description 9
- 229910052763 palladium Inorganic materials 0.000 claims description 9
- 150000002941 palladium compounds Chemical class 0.000 claims description 9
- 230000008878 coupling Effects 0.000 claims description 8
- 238000010168 coupling process Methods 0.000 claims description 8
- 239000012429 reaction media Substances 0.000 claims description 8
- 238000010626 work up procedure Methods 0.000 claims description 8
- 239000002253 acid Substances 0.000 claims description 7
- 238000010511 deprotection reaction Methods 0.000 claims description 7
- 239000003446 ligand Substances 0.000 claims description 7
- 150000003839 salts Chemical class 0.000 claims description 7
- JOXIMZWYDAKGHI-UHFFFAOYSA-M toluene-4-sulfonate Chemical compound CC1=CC=C(S([O-])(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-M 0.000 claims description 7
- 125000005270 trialkylamine group Chemical group 0.000 claims description 7
- 150000001412 amines Chemical class 0.000 claims description 6
- 239000003054 catalyst Substances 0.000 claims description 6
- 239000003795 chemical substances by application Substances 0.000 claims description 6
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 claims description 6
- XGISHOFUAFNYQF-UHFFFAOYSA-N pentanoyl chloride Chemical compound CCCCC(Cl)=O XGISHOFUAFNYQF-UHFFFAOYSA-N 0.000 claims description 6
- 229910000073 phosphorus hydride Inorganic materials 0.000 claims description 6
- 229910002666 PdCl2 Inorganic materials 0.000 claims description 5
- 150000001735 carboxylic acids Chemical class 0.000 claims description 5
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 5
- -1 trimethylsilyl (TMS) groups Chemical group 0.000 claims description 5
- 230000003197 catalytic effect Effects 0.000 claims description 4
- 238000011065 in-situ storage Methods 0.000 claims description 4
- 239000002798 polar solvent Substances 0.000 claims description 4
- 238000006467 substitution reaction Methods 0.000 claims description 4
- NFHFRUOZVGFOOS-UHFFFAOYSA-N Pd(PPh3)4 Substances [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 claims description 3
- 229910052794 bromium Inorganic materials 0.000 claims description 3
- HRXKRNGNAMMEHJ-UHFFFAOYSA-K trisodium citrate Chemical compound [Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O HRXKRNGNAMMEHJ-UHFFFAOYSA-K 0.000 claims description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
- 230000010933 acylation Effects 0.000 claims description 2
- 238000005917 acylation reaction Methods 0.000 claims description 2
- 229910052801 chlorine Inorganic materials 0.000 claims description 2
- 229910052739 hydrogen Inorganic materials 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims description 2
- SIOVKLKJSOKLIF-HJWRWDBZSA-N trimethylsilyl (1z)-n-trimethylsilylethanimidate Chemical group C[Si](C)(C)OC(/C)=N\[Si](C)(C)C SIOVKLKJSOKLIF-HJWRWDBZSA-N 0.000 claims 2
- 101150003085 Pdcl gene Proteins 0.000 claims 1
- 125000003158 alcohol group Chemical group 0.000 claims 1
- 239000003125 aqueous solvent Substances 0.000 claims 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 claims 1
- 229910052731 fluorine Inorganic materials 0.000 claims 1
- 239000003495 polar organic solvent Substances 0.000 claims 1
- 239000000543 intermediate Substances 0.000 abstract description 27
- 206010019280 Heart failures Diseases 0.000 abstract description 2
- 208000037849 arterial hypertension Diseases 0.000 abstract description 2
- 239000003814 drug Substances 0.000 abstract description 2
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 42
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 21
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 18
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 14
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 12
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 10
- JLSJNULDXGXFBC-NSHDSACASA-N (2s)-2-[(4-bromophenyl)methylazaniumyl]-3-methylbutanoate Chemical compound CC(C)[C@@H](C(O)=O)NCC1=CC=C(Br)C=C1 JLSJNULDXGXFBC-NSHDSACASA-N 0.000 description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- 238000004296 chiral HPLC Methods 0.000 description 9
- 239000012071 phase Substances 0.000 description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 8
- 238000010992 reflux Methods 0.000 description 8
- 239000007787 solid Substances 0.000 description 8
- 239000000725 suspension Substances 0.000 description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 7
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 7
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 7
- 239000012299 nitrogen atmosphere Substances 0.000 description 7
- 239000000047 product Substances 0.000 description 7
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 6
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 6
- 239000003480 eluent Substances 0.000 description 6
- 150000004702 methyl esters Chemical class 0.000 description 6
- 238000010898 silica gel chromatography Methods 0.000 description 6
- MQUSOWYDELDFBC-INIZCTEOSA-N (2s)-2-[(4-bromophenyl)methyl-pentanoylamino]-3-methylbutanoic acid Chemical compound CCCCC(=O)N([C@@H](C(C)C)C(O)=O)CC1=CC=C(Br)C=C1 MQUSOWYDELDFBC-INIZCTEOSA-N 0.000 description 5
- 239000012043 crude product Substances 0.000 description 5
- 0 CCCCC(N(Cc1ccc(*)cc1)C(C(C)C)C(O)=O)=O Chemical compound CCCCC(N(Cc1ccc(*)cc1)C(C(C)C)C(O)=O)=O 0.000 description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 4
- 239000008346 aqueous phase Substances 0.000 description 4
- UAEPNZWRGJTJPN-UHFFFAOYSA-N methylcyclohexane Chemical compound CC1CCCCC1 UAEPNZWRGJTJPN-UHFFFAOYSA-N 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- 238000000746 purification Methods 0.000 description 4
- 229910052938 sodium sulfate Inorganic materials 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- UGWULZWUXSCWPX-UHFFFAOYSA-N 2-sulfanylideneimidazolidin-4-one Chemical compound O=C1CNC(=S)N1 UGWULZWUXSCWPX-UHFFFAOYSA-N 0.000 description 3
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 3
- 125000002843 carboxylic acid group Chemical group 0.000 description 3
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 3
- 230000007613 environmental effect Effects 0.000 description 3
- 239000002609 medium Substances 0.000 description 3
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 3
- 235000011152 sodium sulphate Nutrition 0.000 description 3
- 125000002987 valine group Chemical group [H]N([H])C([H])(C(*)=O)C([H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 3
- IJIBRSFAXRFPPN-UHFFFAOYSA-N 5-bromo-2-methoxybenzaldehyde Chemical compound COC1=CC=C(Br)C=C1C=O IJIBRSFAXRFPPN-UHFFFAOYSA-N 0.000 description 2
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 2
- 239000012736 aqueous medium Substances 0.000 description 2
- 150000001540 azides Chemical class 0.000 description 2
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
- 239000004305 biphenyl Substances 0.000 description 2
- 235000010290 biphenyl Nutrition 0.000 description 2
- 230000005587 bubbling Effects 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 230000006872 improvement Effects 0.000 description 2
- GYNNXHKOJHMOHS-UHFFFAOYSA-N methyl-cycloheptane Natural products CC1CCCCCC1 GYNNXHKOJHMOHS-UHFFFAOYSA-N 0.000 description 2
- 230000007935 neutral effect Effects 0.000 description 2
- 230000003287 optical effect Effects 0.000 description 2
- 238000001556 precipitation Methods 0.000 description 2
- 238000009991 scouring Methods 0.000 description 2
- 159000000000 sodium salts Chemical class 0.000 description 2
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 2
- DPJYJNYYDJOJNO-UHFFFAOYSA-N (2s)-bornane-10,2-sultam Chemical compound C1S(=O)(=O)NC2CC3C(C)(C)C12CC3 DPJYJNYYDJOJNO-UHFFFAOYSA-N 0.000 description 1
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- DCERHCFNWRGHLK-UHFFFAOYSA-N C[Si](C)C Chemical compound C[Si](C)C DCERHCFNWRGHLK-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-NJFSPNSNSA-N Carbon-14 Chemical compound [14C] OKTJSMMVPCPJKN-NJFSPNSNSA-N 0.000 description 1
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 1
- 125000003580 L-valyl group Chemical group [H]N([H])[C@]([H])(C(=O)[*])C(C([H])([H])[H])(C([H])([H])[H])[H] 0.000 description 1
- 239000007832 Na2SO4 Substances 0.000 description 1
- DHXVGJBLRPWPCS-UHFFFAOYSA-N Tetrahydropyran Chemical compound C1CCOCC1 DHXVGJBLRPWPCS-UHFFFAOYSA-N 0.000 description 1
- 229960000583 acetic acid Drugs 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 150000003855 acyl compounds Chemical class 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 239000000400 angiotensin II type 1 receptor blocker Substances 0.000 description 1
- 150000001502 aryl halides Chemical class 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 125000004093 cyano group Chemical group *C#N 0.000 description 1
- YNHIGQDRGKUECZ-UHFFFAOYSA-N dichloropalladium;triphenylphosphanium Chemical compound Cl[Pd]Cl.C1=CC=CC=C1[PH+](C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1[PH+](C=1C=CC=CC=1)C1=CC=CC=C1 YNHIGQDRGKUECZ-UHFFFAOYSA-N 0.000 description 1
- 229940074619 diovan Drugs 0.000 description 1
- SXZIXHOMFPUIRK-UHFFFAOYSA-N diphenylmethanimine Chemical compound C=1C=CC=CC=1C(=N)C1=CC=CC=C1 SXZIXHOMFPUIRK-UHFFFAOYSA-N 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000004880 explosion Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 238000007210 heterogeneous catalysis Methods 0.000 description 1
- 238000007172 homogeneous catalysis Methods 0.000 description 1
- 229910001867 inorganic solvent Inorganic materials 0.000 description 1
- 239000003049 inorganic solvent Substances 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- FMKOJHQHASLBPH-UHFFFAOYSA-N isopropyl iodide Chemical compound CC(C)I FMKOJHQHASLBPH-UHFFFAOYSA-N 0.000 description 1
- 238000002372 labelling Methods 0.000 description 1
- HZVOZRGWRWCICA-UHFFFAOYSA-N methanediyl Chemical class [CH2] HZVOZRGWRWCICA-UHFFFAOYSA-N 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 150000003679 valine derivatives Chemical class 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
- C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D257/04—Five-membered rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
- C07C227/18—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C229/34—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton containing six-membered aromatic rings
- C07C229/36—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton containing six-membered aromatic rings with at least one amino group and one carboxyl group bound to the same carbon atom of the carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/02—Preparation of carboxylic acid amides from carboxylic acids or from esters, anhydrides, or halides thereof by reaction with ammonia or amines
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C233/00—Carboxylic acid amides
- C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C233/45—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
- C07C233/46—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
- C07C233/47—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of an acyclic saturated carbon skeleton
Definitions
- This invention relates to a process for preparing intermediates useful for making a pharmaceutically active compound for manufacturing a medicament for treating arterial hypertension or heart failure, and to a process for preparing said pharmaceutically active compound.
- this invention relates to a process for preparing Valsartan, its synthesis intermediates and to the processes for preparing said intermediates.
- Said Spanish patent discloses how it is prepared by converting a phenyl substituent (Z 1 ) into tetrazole, where Z 1 is a group convertible into tetrazole, and can among others be a halogen group.
- Z 1 is a group convertible into tetrazole, and can among others be a halogen group.
- the examples of said patent describe the specific case in which Z 1 is a cyano group or a protected tetrazole ring. This is followed by final deprotection of the carboxylic acid group, where R is preferably methyl or benzyl and, where applicable, of the tetrazole ring protective group, preferably a trityl group.
- Another negative aspect lies in the use of large protective groups for both the tetrazole ring (trityl group) and for the carboxylic acid of the valine moiety (benzyl group), which increase very considerably the molecular weight of the last synthesis intermediate, which is dramatically reduced subsequently in the final hydrolysis to yield Valsartan, resulting in a process of low atomic efficiency. This further creates a considerable amount of residual products and increases the number of synthesis steps in the process.
- Patents DE4313747 , DE4407488 , US5596006 , EP594022 and WO9609301 describe the synthesis of sartans by means of formation of the biphenyl system by reacting an aryl halide with the 2-(1H-tetrazol-5-yl)phenylboronic acid in the presence of a palladium catalyst.
- OEHBERG L. ET AL One-pot three-step solution phase synthesis of thiohydantoins using microwave heating. Synnlett, 2001, 12, 1893-1896 describes a compound where X is Br and R 1 is a group methyl. Said document relates to the use of microwave assisted heating in the context of multi-step solution phase/combinatorial syntheses of thiohydantoins. Neither Valsartan nor intermediate compounds are thiohydantoins.
- MOENIUS T ET AL Carbon-14 labelling of DIOVAN in its valine-moiety.
- J. Labelled Cpd. Radiopharm. 2000, 43, 1245-1252 relates to the synthesis of C-14 labelled Valsartan, which incorporates two C-14 isotopes in the valine-moiety.
- Patent EP 1254899 describes a compound of formula IV where X is F and R 1 is a group methyl.
- a first aspect of this invention is therefore to provide a process for preparing Valsartan that permits it to be obtained with high yields.
- Valsartan is obtained without racemisation problems.
- the last synthesis intermediate of formula (VI) can be obtained with an enantiomeric excess (e.e.) of 100%.
- Valsartan defined in claim 1 uses simple and available starting products that avoid the formation of tetrazole, as the latter is already incorporated into the starting product and there is therefore no need to work with sodium azide in the last synthesis steps, thereby avoiding safety problems in preparing it.
- the process defined in a first aspect of the invention does not use protective groups of tetrazole or of the carboxylic acid group of the valine moiety of the last synthesis intermediate VI.
- This together with the fact that the last synthesis step is a catalytic reaction, favours what is understood as the atomic efficiency of the process, that is, the proportion of atoms of the respective starting reagents that are incorporated into the desired product is optimum and translates into a considerable reduction of the amounts of residues to be treated.
- Valsartan can be obtained with few synthesis steps; in particular, only three steps are necessary if silylating agents are used.
- a second aspect of the invention is the synthesis intermediate defined by formula(IV).
- a third aspect of the invention is the synthesis intermediate defined by formula (V).
- a fourth aspect of the invention is the synthesis intermediate defined by formula (VI).
- a fifth aspect of the invention is to provide another process for preparing the synthesis intermediate of formula (V).
- a sixth aspect of the invention is to provide a process for preparing the synthesis intermediate of formula (VI).
- a seventh aspect of the invention is to provide a process for preparing Valsartan by coupling the advanced intermediate of formula VI with the compound of formula VII. Said process manages to prevent racemisation and is therefore very useful for preparing Valsartan on an industrial scale.
- carboxylic acid protective groups is taken to mean any protective group of carboxylic acids of the optionally substituted methyl or ethyl ester type described in " Protective groups in organic synthesis", T.W. Greene, P.G.M. Wats 3aEd. (1999), page 369 .
- Methyl or ethyl groups are preferably chosen from among the protective groups described.
- leaving group is taken to mean any group that can be displaced by the amine group in intermediates III and VIII.
- the preferable choice is halogen, especially bromine or -OSO 2 R, where R is CF 3 , tolyl, methyl or F.
- organic base is taken to mean a substituted amine type compound.
- the latter is chosen from trialkylamine, especially diisopropylethylamine (DIPEA).
- aprotic organic solvent is taken to mean a solvent that is not capable of exchanging protons with the reagents.
- said aprotic organic solvent is chosen form tetrahydrofuran (THF) or dimethylformamide (DMF), according to the stage of the process.
- palladium catalyst is taken to mean a palladium compound, which can be homogeneous and soluble in the reaction medium, such as Pd(PPh 3 ) 4 , PdCl 2 (PPh 3 ) 4 , PdCl 2 (PPh 3 ) 2 , Pd(AcO) 2 , or heterogeneous and insoluble in the reaction medium, such as Pd/C.
- ligand is taken to mean a phosphine or carbene type compound.
- said ligand is a triarylphosphine type.
- work up is taken to mean the subsequent work of isolation and/or purification following the reaction, in which extractions or precipitations can take place in an aqueous medium.
- one pot is taken to mean a series of consecutive reactions which are carried out without isolating the respective intermediates.
- This invention has the object of providing a new process for preparing Valsartan of formula (I), which permits it to be obtained with good yields and does not present problematic safety or environmental aspects.
- a second aspect of the invention is the synthesis intermediate of formula (IV): where X means halogen or an -OSO 2 R group, where R is CF 3 , tolyl, methyl or F, and R 1 a protective group of carboxylic acids, as long as when X is F Cl or Br, R 1 is other than methyl.
- a third aspect of the invention is the synthesis intermediate of formula (V): where X means halogen or an -OSO 2 R group, where R is CF 3 , tolyl, methyl or F.
- a fourth aspect of the invention is the synthesis intermediate of formula (VI): where X means halogen or an -OSO 2 R group, where R is CF 3 , tolyl, methyl or F.
- a fifth aspect of the invention is to provide an alternative process for preparing the synthesis intermediate of formula (V), which is characterised in that it includes:
- said stages a) and b) are carried out in a "one pot” reaction. This process occurs differently according to the silylating agent chosen.
- said "one pot” reaction includes (Scheme II):
- step a) formation of the p-toluenesulphonate of the L-valine is carried out in a polar solvent, preferably alcohol or water.
- step b) the reaction takes place with 1 equivalent of 1,1,1,3,3,3-hexamethyldisilazane in an aprotic organic solvent under anhydrous conditions, to provide a few stable silylated compound that is not isolated.
- step c) the same aprotic organic solvent is used as in step b), at a temperature of, between 25°C and 150°C, preferably between 40°C and 100°C, and in the presence of an organic base of the trialkylamine type, preferably DIPEA.
- step d) hydrolysis of the trimethylsilyl groups takes place in an aqueous "work-up".
- step a) the reaction of the L-valine takes place with 1 equivalent of ,O-Bis(trimethyl-silyl)acetamide in an aprotic organic solvent, preferably DMF, under anhydrous conditions.
- step b) the same aprotic organic solvent is used as in step a), at a temperature of between 25°C and 150°C, preferably between 40°C and 100°C, and in the presence of an organic base of the trialkylamine type, preferably DIPEA.
- step c) hydrolysis of the trimethylsilyl group takes place in a neutral to acid aqueous medium.
- a sixth aspect of the invention is to provide a process for preparing the synthesis intermediate of formula (VI), characterised in that in consists in N-acylation, without protection of the carboxylic acid of the compound of formula (V), with valeroyl chloride: in the presence of an aprotic organic solvent and an organic or inorganic base and at a temperature of between -20 and 40°C, to give the compound of formula (VI):
- said aprotic organic solvent is tetrahydrofuran (THF) and said inorganic base is NaHCO 3 .
- said acylation is carried out at a temperature of between -10 and 10°C.
- the compound of formula (VI) is achieved with good yields and in few reaction steps [2 steps when the "one pot” reaction is effected in order to obtain the compound of formula (V)] from simple and commercially available raw materials.
- the invention provides a process for preparing the compound of formula (VI) without racemisation, from a compound of formula (V) that does not require protection of the carboxylic acid prior to N-acylation, in which case the final deprotection by means of acid or base hydrolysis provides a product of formula (VI) with 20-35% of undesirable racemisation.
- the compound of formula (VI) is obtained with an optical purity of 99.5-100%, which eventually allows very good quantities of Valsartan to be obtained, and therefore greatly simplifies the subsequent process of purification of said active substance.
- a seventh aspect of the invention is to provide a process for preparing Valsartan, of formula I, by coupling the intermediate of formula VI with the compound of formula VII:
- this coupling takes place without need to use protective groups either for the tetrazole ring of the compound of formula VII or for the carboxylic for the carboxylic acid group of the intermediate of formula VI.
- the reaction is effected in the presence of an organic or inorganic base able to form a salt with the tetrazole ring and in the presence of catalytic amounts of a palladium compound.
- the reaction can be carried out in a polar or aqueous inorganic solvent, or a mixture of water and a water-miscible solvent at a temperature of between 25°C and 150°C, preferably between 50°C and 100°C.
- This coupling can be effected in homogeneous phase, if the palladium compound is soluble in the reaction medium, as is the case of Pd(PPh 3 ) 4 , PdCl 2 (PPh 3 ) 4 , PdCl 2 (PPh 3 ) 2 , Pd(ACO) 2 , or in heterogeneous phase if the palladium compound is insoluble in the reaction medium, as in the case of Pd/C.
- the coupling reaction requires the presence of catalytic amounts of a ligand, preferably of the phosphine type, especially triphenylphosphine or a water-soluble phosphine such as the trisodium salt of 3,3',3"-phosphinidinatris (benzenesulphonate).
- a ligand preferably of the phosphine type, especially triphenylphosphine or a water-soluble phosphine such as the trisodium salt of 3,3',3"-phosphinidinatris (benzenesulphonate).
- Valsartan is advantageously obtained with good chemical yield and high optical purity, by means of a process applicable on an industrial scale and starting from simple and commercially available products through synthesis intermediates that do not require protection of the tetrazole ring or of the carboxylic acid of the L-valine moiety, nor the use of sodium azide or tributyl tannic azide, with consequent improvement in the safety of the process and respect for the environment.
- a mixture made up of 5 g (20 mmol) 4-bromobenzylo bromide, 4.02 g (24 mmol) methyl ester hydrochloride of the L-valine and 7.7 mL (44.2 mmol) of diisopropylethylamine in 4.75 mL of dimethylformamide is heated to 90°C. After 1 h at 90°C the mixture is cooled to 20-25°C, 20 mL of toluene is added and it is washed twice with 10 mL of water.
- a mixture made up of 5 g (17.47 mmol) of N-(4-bromobenzyl)-L-valine and 5.9 g (70.24 mmol) of sodium bicarbonate in 50 mL of dry THF is left under stirring and under nitrogen atmosphere for one hour.
- the preceding suspension is cooled to 0°C and to it is added over a period of 15 min.
- the mixture is then left to react at 20-25°C for 3 h, 50 mL of water is added and the THF is distilled at low pressure.
- the resulting solution is taken to pH 2 with HCl 35% and the remains of THF distilled off completely.
- N-(4-iodobenzyl)-N-valeryl-L-valine is obtained from 10 g (30.01 mmol) of N-(4-iodobenzyl)-L-valine and 7.12 mL (60.03 mmol) of valeroyl chloride.
- the solid is recrystallised from a mixture of EtOH/H 2 O 2:1.
- M.p. 126-127°C
- Example 7 Obtaining (S)-N-(1-carboxy-2-methyl-pro-1-yl) -N-pentanoyl-N- (2'-(1H-tetrazol-5-yl-)- biphenyl-4-yl methyl] amine (Valsartan)
- a solution made up of 20 g of crude Valsartan obtained according to example 7 (2) dissolved in 160 mL of AcOEt is treated with 1 g of neutral activated carbon at 45-50°C for 1 h.
- the mixture is filtered, and to the clear solution obtained methylcyclohexane is added slowly at 20-25°C until precipitation is observed (approximately 120 mL).
- the mixture thickens at first, and later a fluid suspension is obtained, at which time the slow addition of a further 120 mL of methylcyclohexane is continued.
- the mixture is left stirring at 20-25°C for 3 h, is filtered and dried in a vacuum oven at 45°C to provide 14 g of Valsartan as a white solid.
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Abstract
Description
- This invention relates to a process for preparing intermediates useful for making a pharmaceutically active compound for manufacturing a medicament for treating arterial hypertension or heart failure, and to a process for preparing said pharmaceutically active compound.
- In particular, this invention relates to a process for preparing Valsartan, its synthesis intermediates and to the processes for preparing said intermediates.
-
- Said Spanish patent discloses how it is prepared by converting a phenyl substituent (Z1) into tetrazole, where Z1 is a group convertible into tetrazole, and can among others be a halogen group. The examples of said patent describe the specific case in which Z1 is a cyano group or a protected tetrazole ring. This is followed by final deprotection of the carboxylic acid group, where R is preferably methyl or benzyl and, where applicable, of the tetrazole ring protective group, preferably a trityl group.
- That patent leaves room for improvement of aspects such as the utilisation of azide in the last synthesis steps, with the attendant risk of explosion if sodium azide is used or environmental problems if tributyl tin azide is used.
- Another negative aspect lies in the use of large protective groups for both the tetrazole ring (trityl group) and for the carboxylic acid of the valine moiety (benzyl group), which increase very considerably the molecular weight of the last synthesis intermediate, which is dramatically reduced subsequently in the final hydrolysis to yield Valsartan, resulting in a process of low atomic efficiency. This further creates a considerable amount of residual products and increases the number of synthesis steps in the process.
-
- OEHBERG L. ET AL: One-pot three-step solution phase synthesis of thiohydantoins using microwave heating. Synnlett, 2001, 12, 1893-1896 describes a compound where X is Br and R1 is a group methyl. Said document relates to the use of microwave assisted heating in the context of multi-step solution phase/combinatorial syntheses of thiohydantoins. Neither Valsartan nor intermediate compounds are thiohydantoins.
- MOENIUS T ET AL: Carbon-14 labelling of DIOVAN in its valine-moiety. J. Labelled Cpd. Radiopharm. 2000, 43, 1245-1252 relates to the synthesis of C-14 labelled Valsartan, which incorporates two C-14 isotopes in the valine-moiety. Reaction of (-)-bromo-[1,2-C]acetyl borname-10.2-sultam ((-)-[C2]BABS) with benzophenone imine gave (-)-diphenyl-methylene(1,2-C2]glycinyl bornane-10.2-sultam ((-)-[C2]DPMGBS), which was alkylated with 2-iodopropane to build-up the valine structure. Then, the valine derivative reacts with a biphenyl compound represented by reference (12).
- Patent
EP 1254899 describes a compound of formula IV where X is F and R1 is a group methyl. - A safe, ecological and high-yield process for obtaining Valsartan with few synthesis steps and using simple and commercially available starting products therefore remains necessary. Additionally, it must be possible to apply said process on an industrial scale and avoiding racemisation and the consequent separation of enantiomers.
- A first aspect of this invention is therefore to provide a process for preparing Valsartan that permits it to be obtained with high yields. Surprisingly, with the process defined in accordance with the first aspect of the invention, Valsartan is obtained without racemisation problems. In particular, the last synthesis intermediate of formula (VI) can be obtained with an enantiomeric excess (e.e.) of 100%.
- Also advantageously, the process for preparing Valsartan defined in claim 1 uses simple and available starting products that avoid the formation of tetrazole, as the latter is already incorporated into the starting product and there is therefore no need to work with sodium azide in the last synthesis steps, thereby avoiding safety problems in preparing it.
- It is furthermore a very clean process from the environmental point of view, as the penultimate synthesis step does not involve the use of tributyl tin azide, which produces large amounts of a toxic by-product, or hexabutyl ditannic oxane, with the attendant problems of treating residues of this type.
- More advantageously still, the process defined in a first aspect of the invention does not use protective groups of tetrazole or of the carboxylic acid group of the valine moiety of the last synthesis intermediate VI. This, together with the fact that the last synthesis step is a catalytic reaction, favours what is understood as the atomic efficiency of the process, that is, the proportion of atoms of the respective starting reagents that are incorporated into the desired product is optimum and translates into a considerable reduction of the amounts of residues to be treated.
- In accordance with the process according to the first aspect of the invention, Valsartan can be obtained with few synthesis steps; in particular, only three steps are necessary if silylating agents are used.
- A second aspect of the invention is the synthesis intermediate defined by formula(IV).
- A third aspect of the invention is the synthesis intermediate defined by formula (V).
- A fourth aspect of the invention is the synthesis intermediate defined by formula (VI).
- A fifth aspect of the invention is to provide another process for preparing the synthesis intermediate of formula (V).
- A sixth aspect of the invention is to provide a process for preparing the synthesis intermediate of formula (VI).
- A seventh aspect of the invention is to provide a process for preparing Valsartan by coupling the advanced intermediate of formula VI with the compound of formula VII. Said process manages to prevent racemisation and is therefore very useful for preparing Valsartan on an industrial scale.
- In this invention, the term "carboxylic acid protective groups" is taken to mean any protective group of carboxylic acids of the optionally substituted methyl or ethyl ester type described in "Protective groups in organic synthesis", T.W. Greene, P.G.M. Wats 3aEd. (1999), page 369. Methyl or ethyl groups are preferably chosen from among the protective groups described.
- The term "leaving group" is taken to mean any group that can be displaced by the amine group in intermediates III and VIII. Among the leaving groups described, the preferable choice is halogen, especially bromine or -OSO2R, where R is CF3, tolyl, methyl or F.
- The term "organic base" is taken to mean a substituted amine type compound. Preferably, the latter is chosen from trialkylamine, especially diisopropylethylamine (DIPEA).
- The term "aprotic organic solvent" is taken to mean a solvent that is not capable of exchanging protons with the reagents. Preferably, said aprotic organic solvent is chosen form tetrahydrofuran (THF) or dimethylformamide (DMF), according to the stage of the process.
- The term "palladium catalyst" is taken to mean a palladium compound, which can be homogeneous and soluble in the reaction medium, such as Pd(PPh3)4, PdCl2(PPh3)4, PdCl2 (PPh3)2, Pd(AcO)2, or heterogeneous and insoluble in the reaction medium, such as Pd/C.
- The term "ligand" is taken to mean a phosphine or carbene type compound. Preferably, said ligand is a triarylphosphine type.
- The term "work up" is taken to mean the subsequent work of isolation and/or purification following the reaction, in which extractions or precipitations can take place in an aqueous medium.
- The term "one pot" is taken to mean a series of consecutive reactions which are carried out without isolating the respective intermediates.
-
- The process for preparing Valsartan in accordance with the first aspect of the invention is characterised in that it includes the following stages (Scheme I):
- a) Displacement of the Y group of a compound of formula (II) by the protected L-valine of formula (III):
- X means halogen or an -OSO2R group, in which R is CF3, tolyl, methyl or F;
- Y means any leaving group that can be displaced by the amine of the compound of formula (III); and
- R1 means a protective group of carboxylic acids, at a temperature between 25°C and 150°C, preferably between 40 and 100°C, and in the presence of an aprotic organic solvent, preferably dimethylformamide (DMF), and an organic base, preferably a trialkylamine, more preferably DIPEA, or an inorganic base, preferably an inorganic base capable of picking up the HY acid given off in the substitution, to give a compound of formula (IV):
- b) Deprotection of the R1 group of the compound of formula (IV), preferably by means of hydrolysis in an acid or basic medium, in order to give the compound of formula (V) :
- c) N-acylation of the compound of formula (V) with valeroyl chloride in an aprotic organic solvent medium, preferably tetrahydrofuran (THF), in the presence of an organic or inorganic base, preferably NaHCO3, and at a temperature ranging between -20 and 40°C, preferably between -10 and 10°C, to give the compound of formula (VI):
- d) Coupling of the compound of formula (VI) with the 2-(1H-tetrazol-5-yl)phenylboronic acid (obtained in accordance with the process described in patent
DE 4313737 ), of formula (VII): -
-
-
-
- A fifth aspect of the invention is to provide an alternative process for preparing the synthesis intermediate of formula (V), which is characterised in that it includes:
- a) Displacement of the Y group of a compound of formula (II) by the L-valine protected by trimethylsilyl groups(TMS) of formula (VIII):
- X means halogen or an -OSO2R groups where R is CF3, tolyl, methyl or F;
- Y means any leaving group capable of being displaced by the amine of the compound VIII; and
- R1 means hydrogen or a trimethylsilyl (TMS) group,
- b) Deprotection of the TMS groups of the compound of formula (IX) in an aqueous "work-up", to give finally the compound of formula (V):
- Advantageously, said stages a) and b) are carried out in a "one pot" reaction. This process occurs differently according to the silylating agent chosen.
- Thus, where the silylating agent is 1,1,1,3,3,3-hexamethyldisilazane (HMDS), said "one pot" reaction includes (Scheme II):
- a) Prior formation of the p-toluenesulphonate of the L-valine in a polar solvent;
- b) "In situ" protection of the p-toluenesulphonate of the L-valine with one equivalent of 1,1,1,3,3,3-hexamethyldisilazane (HMDS) (A. Arrieta; Syn. Commun. 1050-52 (1982)) in the presence of an aprotic organic solvent under anhydrous conditions;
- c) Displacement of the Y group of the compound of formula (II) at a temperature of between 25 and 150°C and in the presence of an organic base; and
- d) Hydrolysis of the trimethylsilyl groups in an aqueous "work-up", to give the compound of formula (V).
-
- In said synthesis, in step a) formation of the p-toluenesulphonate of the L-valine is carried out in a polar solvent, preferably alcohol or water. In step b) the reaction takes place with 1 equivalent of 1,1,1,3,3,3-hexamethyldisilazane in an aprotic organic solvent under anhydrous conditions, to provide a few stable silylated compound that is not isolated. In step c) the same aprotic organic solvent is used as in step b), at a temperature of, between 25°C and 150°C, preferably between 40°C and 100°C, and in the presence of an organic base of the trialkylamine type, preferably DIPEA. And finally, in step d) hydrolysis of the trimethylsilyl groups takes place in an aqueous "work-up".
- Moreover, when ,O-bis,(trimethylsilyl)acetamide (BSA) is chosen as silylating agent, said "one pot" reaction comprises(Scheme III):
- a) "In situ" protection of the carboxylic acid of the L-valine with 1 equivalent of ,O-Bis(trimethylsilyl)-acetamide (BSA) (J.F. Klebe; J. Am. Chem. Soc. 88, 3390-95 (1966))in the presence of an aprotic organic solvent under anhydrous conditions.
- b) Displacement of the Y group of the compound of formula (II) at a temperature of between 25 and 150°C and in the presence of an organic base;
- c) Hydrolysis of the trimethylsilyl group in an aqueous "work-up" to give the compound of formula (V).
-
- In said synthesis, in step a) the reaction of the L-valine takes place with 1 equivalent of ,O-Bis(trimethyl-silyl)acetamide in an aprotic organic solvent, preferably DMF, under anhydrous conditions. In step b) the same aprotic organic solvent is used as in step a), at a temperature of between 25°C and 150°C, preferably between 40°C and 100°C, and in the presence of an organic base of the trialkylamine type, preferably DIPEA. And finally, in step c) hydrolysis of the trimethylsilyl group takes place in a neutral to acid aqueous medium.
- A sixth aspect of the invention is to provide a process for preparing the synthesis intermediate of formula (VI), characterised in that in consists in N-acylation, without protection of the carboxylic acid of the compound of formula (V), with valeroyl chloride:
- Advantageously, said aprotic organic solvent is tetrahydrofuran (THF) and said inorganic base is NaHCO3.
- Also advantageously, said acylation is carried out at a temperature of between -10 and 10°C.
- With the process according to the sixth aspect of the invention the compound of formula (VI) is achieved with good yields and in few reaction steps [2 steps when the "one pot" reaction is effected in order to obtain the compound of formula (V)] from simple and commercially available raw materials.
- Surprisingly and unexpectedly, the invention provides a process for preparing the compound of formula (VI) without racemisation, from a compound of formula (V) that does not require protection of the carboxylic acid prior to N-acylation, in which case the final deprotection by means of acid or base hydrolysis provides a product of formula (VI) with 20-35% of undesirable racemisation.
- Advantageously, the compound of formula (VI) is obtained with an optical purity of 99.5-100%, which eventually allows very good quantities of Valsartan to be obtained, and therefore greatly simplifies the subsequent process of purification of said active substance.
-
- Advantageously, this coupling takes place without need to use protective groups either for the tetrazole ring of the compound of formula VII or for the carboxylic for the carboxylic acid group of the intermediate of formula VI. The reaction is effected in the presence of an organic or inorganic base able to form a salt with the tetrazole ring and in the presence of catalytic amounts of a palladium compound. The reaction can be carried out in a polar or aqueous inorganic solvent, or a mixture of water and a water-miscible solvent at a temperature of between 25°C and 150°C, preferably between 50°C and 100°C. This coupling can be effected in homogeneous phase, if the palladium compound is soluble in the reaction medium, as is the case of Pd(PPh3)4, PdCl2 (PPh3) 4, PdCl2 (PPh3)2, Pd(ACO)2, or in heterogeneous phase if the palladium compound is insoluble in the reaction medium, as in the case of Pd/C. If Pd/C is used, the coupling reaction requires the presence of catalytic amounts of a ligand, preferably of the phosphine type, especially triphenylphosphine or a water-soluble phosphine such as the trisodium salt of 3,3',3"-phosphinidinatris (benzenesulphonate). The latter has the advantage of allowing the reaction to be carried out using water as solvent.
- In this invention Valsartan is advantageously obtained with good chemical yield and high optical purity, by means of a process applicable on an industrial scale and starting from simple and commercially available products through synthesis intermediates that do not require protection of the tetrazole ring or of the carboxylic acid of the L-valine moiety, nor the use of sodium azide or tributyl tannic azide, with consequent improvement in the safety of the process and respect for the environment.
- There follow some examples which show non-restrictively some preferred embodiments of the various
- A mixture made up of 5 g (20 mmol) 4-bromobenzylo bromide, 4.02 g (24 mmol) methyl ester hydrochloride of the L-valine and 7.7 mL (44.2 mmol) of diisopropylethylamine in 4.75 mL of dimethylformamide is heated to 90°C. After 1 h at 90°C the mixture is cooled to 20-25°C, 20 mL of toluene is added and it is washed twice with 10 mL of water. The organic phase is dried with anhydrous sodium sulphate and concentrated in vacuo to dryness to provide 5.7g (95%) of the methyl ester of N-(4-bromobenzyl)-L-valine in the form of an oil.
IR (film, cm-1): 3350, 2980, 1740, 1490, 1200, 1180, 1150, 1010.
NMR 1H (CDCl3), δ (ppm) : 0.93 (dd, 6H, -CH(CH3)2), 1.8-2.0 (m, 1H, -CH(CH3)2), 2.95 (d, 1H, -CH-COOCH3), 3.4-3.9 (dd, 2H, Ar-CH2-), 3.75 (s, 3H, -COOCH3), 7.25 (d, 2H, ArH), 7.45 (d, 2H, ArH). - In a similar way to that of example 1, 2.3 g (98.3%) of the methyl ester of N-(4-iodobenzyl)-L-valine is prepared from 2 g (6.74 mmol) of 4-iodobénzylo bromide.
IR (film, cm-1): 3330, 2980, 1740, 1480, 1200, 1180, 1150, 1010.
NMR 1H (CDCl3), δ (ppm): 0.93 (dd, 6H, -CH(CH 3)2) , 1.8-2.0 (m, 1H, -CH(CH3)2), 2.95 (d, 1H, -CH-COOCH3), 3.4-3.9 (dd, 2H, Ar-CH 2-), 3.7 (s, 3H, -COOCH 3), 7.1 (d, 2H, ArH), 7.6 (d, 2H, ArH). -
- (1) A mixture made up of 1.34 g (4.45 mmol) of the methyl ester of N-(4-bromobenzyl)-L-valine obtained in example 1 and 0.62 g (9.39 mmol) of 85% KOH dissolved in 15 mL of methanol and 1 mL of water is heated at reflux. After maintaining the reaction for 3 h at reflux, it is cooled to 20-25°C and acidified to pH 4-5 with HCl 1N. After stirring the suspension for 1 h at 20-25°C, it is filtered and washed with water to provide 1 g (78.3%) of N-(4-bromobenzyl)-L-valine. M.p. = 239-241°C
The enantiomeric purity is determined by chiral HPLC, giving e.e. = 98.56%
IR (KBr, cm-1): 2950, 1610, 1490, 1470, 1390, 1210, 1030, 840.
NMR 1H (D2O), sodium salt of N-(4-bromobenzyl)-L-valine, δ (ppm): 0.90 (t, 6H, -CH (CH3)2) , 1.7-1 . 9 (m, 1H, - CH(CH3)2), 2.83 (d, 1H, -CH-COONa), 3.4-3.8 (dd, 2H, Ar-CH 2-), 7.27 (d, 2H, ArH), 7.55 (d, 2H, ArH). - (2) To a suspension of 10 g (34.6 mmol) of p-toluenesulphonate of L-valine in 100 mL of CH2Cl2 is added at 20-25°C and under nitrogen atmosphere 8.0 mL (38 mmol) of 1,1,1,3,3.3-hexamethyldisilazane. After shaking the mixture at 20-25°C for one hour, 13.2 mL (76 mmol) of diisopropylethylamine and 8.64 g (34.6 mmol) of 4-bromobenzylo bromide are added and heated at reflux. When all the 4-bromobenzylo bromide has been consumed, the solvent is evaporated off at low pressure, 100 mL of water is added and after 1h at 0°C the solid is filtered and dried in an air oven at 40°C to provide 8.8 g (89%) of N-(4-bromobenzyl)-L-valine.
The enantiomeric purity is determined by chiral HPLC, giving e.e. = 100% - (3) 52 mL (0.21 mol) of O-bistrimethylsilylacetamide is added under nitrogen atmosphere to a mixture made up of 23.5 g (0.20 mol) of L-valine and 38.5 mL (0.22 mol) of diisopropylethylamine in 12.5 mL of DMF. After 1h at 80°C the suspension changes to a clear solution. Then, in portions and controlling exothermy, 50 g (0.20 mol) of 4-bromobenzylo bromide is added and left to react at 80°C for 2 h. The mixture is cooled to 20-25°C, 250 mL of toluene and a solution made up of 250 mL of water and 80 mL of NaOH 40% are added. The resulting aqueous phase is washed twice with 100 mL of AcOEt, the remains of solvent distilled and taken to pH 6-7 with HC1 3N. The solid obtained is filtered with 250 mL of IPA to give 43.9 g (76.5%) of N-(4-bromobenzyl)-L-valine.
The enantiomeric purity is determined by chiral HPLC, giving e.e. = 100% -
- (1) A mixture made up of 2.3 g (6.62 mmol) of the methyl ester of N-(4-iodobenzyl)-L-valine obtained in example 2 and 0.92 g (13.94 mmol) of 85% KOH dissolved in 23 mL of methanol and 2 mL of water is heated at reflux. After maintaining the reaction for 5 h at reflux, it is cooled to 20-25°C and acidified to pH 7 with HCl 1N. After stirring the suspension for 1 h at 20-25°C, it is filtered with water to provide 1.8 g (82.2%) of N-(4-iodobenzyl)-L-valine. M.p. = 256-258°C
The enantiomeric purity is determined by chiral HPLC, giving e.e. = 99.38%
IR (KBr, cm-1) : 2960, 1610, 1490, 1460, 1410, 1210, 1005, 830.
NMR 1H (D2O), sodium salt of N-(4-iodobenzyl)-L-valine, δ (ppm): 0.90 (t, 6H, -CH(CH 3)2) , 1.7-1.9 (m, 1H, - CH(CH3)2), 2.84 (d, 1H, -CH-COONa), 3.4-3.8 (dd, 2H, ArCH2-) , 7.15 (d, 2H, ArH), 7.75 (d, 2H, ArH). - (2) To a suspension of 12 g (41.5 mmol) of p-toluenesulphonate of L-valine in 120 mL of CH2Cl2 is added at 20-25°C and under nitrogen atmosphere 9.6 mL (45.5 mmol) of 1,1,1,3,3,3-hexamethyldisilazane. After shaking the mixture at 20-25°C for 2 h, 15.9 mL (91.3 mmol) of diisopropylethylamine and 12.3 g (41.5 mmol) of 4-iodobenzylo bromide are added and heated at reflux. When all the 4-iodobenzylo bromide has been consumed the solvent is evaporated off at low pressure, 120 mL of water is added and after 1h at 0°C the solid is filtered and dried in an air oven at 40°C to provide 11.6 g (84%) of N-(4-iodobenzyl)-L-valine.
The enantiomeric purity is determined by chiral HPLC, giving e.e. = 100% - (3) 45.8 mL (0.185 mol) of ,O-bistrimethylsilylacetamide is added under nitrogen atmosphere to a mixture made up of 21.7 g (0.185 mol) of L-valine and 32.3 mL (0.185 mol) of diisopropylethylamine in 12.5 mL of DMF. After 1h at 80°C the suspension becomes a clear solution. Then, 50 g (0.168 mol) of 4-iodobenzylo bromide is added in portions at 50°C and controlling exothermy, and it is left to react at 80°C for 2 h. The mixture is cooled to 20-25°C, and 250 mL of toluene and a solution made up of 250 mL of water and 80 mL of NaOH 40% is added. The resulting aqueous phase is washed twice with 100 mL of AcOEt, the remains of solvent are distilled and it is taken to pH 6-7 with HCl 3N. The solid obtained is filtered with 250 mL of IPA to give 47.9 g (85.3%) of N-(4-iodobenzyl)-L-valine.
The enantiomeric purity is determined by chiral HPLC, giving e.e. = 100% - A mixture made up of 5 g (17.47 mmol) of N-(4-bromobenzyl)-L-valine and 5.9 g (70.24 mmol) of sodium bicarbonate in 50 mL of dry THF is left under stirring and under nitrogen atmosphere for one hour. The preceding suspension is cooled to 0°C and to it is added over a period of 15 min. 4.2 mL (35.41 mmol) of valeroyl chloride. The mixture is then left to react at 20-25°C for 3 h, 50 mL of water is added and the THF is distilled at low pressure. The resulting solution is taken to pH 2 with HCl 35% and the remains of THF distilled off completely. The solid obtained is filtered, washed with 50 mL of water and dried in a vacuum over to provide 5.9 g (91.2%) of N-(4-bromobenzyl)-N-valeryl-L-valine. The solid is recrystallised from a mixture of EtOH/H2O 2:1. M.p. = 123°C
- The enantiomeric purity is determined by chiral HPLC, giving e.e. > 98%
IR (KBr, cm-1) : 2960, 1720, 1590, 1480, 1420, 1250.
NMR 1H (CDCl3) , δ (ppm): 0.8-1.1 (m, 9H, -CH (CH 3) 2 + - CH2CH 3), 1.2-1.5 (m, 2H, -CH 2CH3) , 1.5-1.8 (m, 2H, - CH2CH2CH3), 2.4 (m, 2H, -CH2CO-), 2.7 (m, 1H, -CH(CH3)2), 3.7 (d, 1H, -CH-COOH), 4.3-4.8 (dd, 2H, Ar-CH2-), 7.1 (d, 2H, ArH), 7.5 (d, 2H, ArH). - In a manner analogous to example 5, 11.5 g (91.8%) of N-(4-iodobenzyl)-N-valeryl-L-valine is obtained from 10 g (30.01 mmol) of N-(4-iodobenzyl)-L-valine and 7.12 mL (60.03 mmol) of valeroyl chloride. The solid is recrystallised from a mixture of EtOH/H2O 2:1. M.p. = 126-127°C
- The enantiomeric purity is determined by chiral HPLC, giving e.e. > 99%
IR (KBr, cm-1): 2960, 1725, 1595, 1480, 1405, 1255.
NMR 1H (CDCl3) , δ (ppm) : 0.8-1.1 (m, 9H, -CH (CH 3)2 + -CH2CH 3), 1.2-1.5 (m, 2H, -CH 2CH3), 1.5-1.8 (m, 2H, - CH 2CH2CH3), 2.4 (m, 2H, -CH2CO-), 2.7 (m, 1H, -CH(CH3)2), 3.7 (d, 1H, -CH-COOH), 4.3-4.8 (dd, 2H, Ar-CH2-), 6.9 (d, 2H, ArH), 7.7 (d, 2H, ArH). -
- (1) To a mixture made up of 1.35 mL of ethanol, 13.5.mL of 1.2-dimethoxyethane and 4 mL of water are added 0.50 g (1.35 mmol) of N-(4-bromobenzyl)-N-valeryl-L-valine, 0.308 g (1.62 mmol) of 2-(1H-tetrazol-5-yl)phenylboronic acid, 0.156 g (0.135 mmol) of palladium tetrakistriphenylphosphine and 0.324 g (8.1 mmol) of NaOH. The mixture, following scouring with gentle bubbling of nitrogen for 5 min, is heated at reflux for 12 h. The reaction is cooled to 20-25°C and 25 mL of AcOEt and 25 mL of water are added. The decanted aqueous phase is taken to pH 1-2 with HCl 37% and extracted with 25 mL of AcOEt. After evaporating the AcOEt phase to dryness and purifying by silica gel chromatography (eluent AcOEt/heptane/AcOH 15:5:0.2) 0.356 g (60.5%) of Valsartan is obtained.
NMR 1H (CDCl3), δ (ppm): 0.8-1.1 (m, 9H, -CH(CH3)2 + - CH2CH 3), 1.3-1.5 (m, 2H, -CH 2CH3), 1.5-1.8 (m, 2H, - CH 2CH2CH3), 2.6 (t, 2H, -CH2CO-), 2.7 (m, 1H, -CH(CH3)2), 3.5 (d, 1H, -CH-COOH), 4.3-5.0 (dd, 2H, Ar-CH2-), 7.0-7.7 (m, 7H, ArH), 8.0-8.1 (d, 1H, ArH in ortho position to the tetrazole ring). - (2) To a mixture made up of 3 mL of methanol, 0.9 mL of water and 0.096 g (2.4 mmol) of NaOH are added 0.250 g (0.60 mmol) of N-(4-iodobenzyl)-N-valeryl-L-valine, 0.137 g (0.72 mmol) of 2-(1H-tetrazol-5-yl)phenylboronic acid and 0.035 g (0.030 mmol) of palladium tetrakistriphenylphosphine. Following scouring with gentle bubbling of nitrogen for 5 min, the mixture is heated at reflux for 2 h. The reaction is cooled to 20-25°C, the methanol is distilled in vacuo and 25 mL of AcOEt and 25 mL of water are added. The decanted aqueous phase is taken to pH 1-2 with HCl 37% and extracted with 25 mL of AcOEt. After evaporating the AcOEt phase to dryness and purifying by silica gel chromatography (eluent AcOEt/heptane/AcOH 15:5:0.2) 0.230 g (88%) of Valsartan is obtained.
- (3) Nitrogen is bubbled for 5 min. To a mixture made up of 0.50 g (1.35 mmol) of N-(4-bromobenzyl)-N-valeryl-L-valine, 0.308 g (1.62 mmol) of 2-(1H-tetrazol-5-yl)phenylboronic acid, 0.0028 g (0.016 mmol) of palladium chloride and 0.0084 g (0.032 mmol) of triphenylphosphine in a solution of 2.06 mL (13.0 mmol) of sodium methoxide in methanol al 30% and 5 mL of methanol are added. It is heated at 70°C under nitrogen atmosphere for 5 h, 0.050 g of activated carbon is added and it is stirred at the same temperature for a further 15 min. After cooling to 20-25°C it is filtered, the methanol is evaporated and it is treated with 25 mL of HCl 1N and 25 mL of AcOEt. The AcOEt phase is dried with anhydrous sodium sulphate and after distilling the solvent the crude product obtained is purified by silica gel chromatography (eluent AcOEt/heptane/AcOH 15:5:0.2) to provide 0.327 g (55.6%) of Valsartan.
- (4) Nitrogen is bubbled for 5 min. To a mixture made up of 0.20 g (0.48 mmol) of N-(4-iodobenzyl)-N-valeryl-L-valine, 0.115 g (0.61 mmol) of 2-(1H-tetrazol-5-yl)phenylboronic acid, 0.017 g (0.024 mmol) of bis(triphenylphosphine)palladium chloride and 0.115 g (2.87 mmol) of NaOH in 2.4 mL of methanol and 0.7 mL of water are added. The reaction is heated to 70°C under nitrogen atmosphere. Once 3 h has elapsed the reaction is considered to be completed and the methanol is distilled. The crude product is treated with 25 mL of HCl 1N and 25 mL of AcOEt. The AcOEt phase is dried with anhydrous sodium sulphate and after distilling the solvent the crude product obtained is purified by silica gel chromatography (eluent -AcOEt/heptane/AcOH 15:5:0.2) to provide 0.178 g (85%) of Valsartan.
-
- (5) A mixture made up of 1 g (2.70 mmol) of N-(4-bromobenzyl)-N-valeryl-L-valine, 0.513 g (2.70 mmol) of 2-(1H-tetrazol-5-yl)phenylboronic acid, 0.120 g of 5% Pd/C in paste (0.028 mmol of palladium) and 0.0084 g (0.032 mmol) of triphenylphosphine in a solution of 4.1 mL (21.5 mmol) of sodium methoxide in 30% methanol and 10 mL of methanol is heated at 70°C for 10 h. The reaction is cooled to 20-25°C, the catalyst is filtered and the methanol distilled in vacuo. The resulting residue is dissolved in 25 mL of water and, following washing with 25 mL of AcOEt, is acidified to pH 3 with HCl 3N and extracted twice with 20 mL of AcOEt. The combined phases of AcOEt are dried with anhydrous Na2SO4 and following distillation of the solvent the crude product obtained is purified by silica gel chromatography (eluent AcOEt/heptane/AcOH 15:5:0.2) to provide 0.683 g (58%) of Valsartan.
In an analogous way, 0.745 g (71.4%) of Valsartan is obtained from 1 g (2.4. mmol) of N-(4-iodobenzyl)-N-valeryl-L-valine, 0.546 g (2.88 mmol) of 2-(1H-tetrazol-5-yl)phenylboronic acid, 0.120 g of 5% Pd/C in paste (0.028 mmol of palladium) and 0.0074 g (0.028 mmol) of triphenylphosphine in a solution of 3.7 mL (19.4 mmol) of sodium methoxide in methanol at 30% and 10 mL of methanol. - (6) A mixture made up of 0.1 g (0.24 mmol) of N-(4-iodobenzyl)-N-valeryl-L-valine, 0.055 g (0.29 mmol) of 2-(1H-tetrazol-5-yl)phenylboronic acid, 0.038 g (0.95 mmol) of NaOH, 0.0102 g of 5% Pd/C in paste (0.0024 mmol of palladium) and 0.0020 g (0.0035 mmol) of the trisodium salt of 3,3',3''-phosphinidinatris(benzenesulphonate) in 1 mL of water is heated at 70°C for 2 h. After cooling the mixture to 20-25°C the catalyst is filtered and 0.1 mL of glacial acetic acid is added to provide, once filtered and dried in an air oven at 45°C, 0.086 g of crude Valsartan. Following purification of this crude product by silica gel chromatography (eluent AcOEt/heptane/AcOH 15:5:0.2) 0.072 g (68%) of Valsartan is obtained.
- A solution made up of 20 g of crude Valsartan obtained according to example 7 (2) dissolved in 160 mL of AcOEt is treated with 1 g of neutral activated carbon at 45-50°C for 1 h. The mixture is filtered, and to the clear solution obtained methylcyclohexane is added slowly at 20-25°C until precipitation is observed (approximately 120 mL). The mixture thickens at first, and later a fluid suspension is obtained, at which time the slow addition of a further 120 mL of methylcyclohexane is continued. The mixture is left stirring at 20-25°C for 3 h, is filtered and dried in a vacuum oven at 45°C to provide 14 g of Valsartan as a white solid.
- La enantiomeric purity is determined by chiral HPLC, giving e.e. >99.5%
Claims (25)
- Process for preparing a pharmaceutically active compound, Valsartan, or a pharmaceutically acceptable salt thereof, characterised in that it includes the following stages:a) Displacement of the Y group of a compound of formula (II) by the protected L-valine of formula (III) :X means halogen or an -OSO2R group, where R is CF3, tolyl, methyl or F;Y means any leaving group capable of being displaced by the amine of the compound of formula (III); andR1 means a protective group of carboxylic acids,at a temperature of between 25°C and 150°C and in the presence of an aprotic organic solvent and an organic base or an inorganic base to give a compound of formula (IV):b) Deprotection of the R1 group of the compound of formula (IV) to give the compound of formula (v) :c) N-acylation of the compound of formula (V) with valeroyl chloride in an aprotic organic solvent medium, in the presence of an organic or inorganic base and at a temperature of between -20 and 40°C, to give the compound of formula (VI) :d) Coupling of the compound of formula (VI) with the 2-(1H-tetrazol-5-yl)phenylboronic acid, of formula (VII):
- Process according to Claim 1, characterised in that in said stage a) said displacement is carried out at a temperature of between 40 and 100°C, in the presence of dimethylformamide (DMF) and an organic base selected from trialkylamine, preferably DIPEA, or an inorganic base selected from an inorganic base capable of picking up the HY given off in the substitution.
- Process according to Claim 1, characterised in that in said stage b) said deprotection is carried out by means of hydrolysis in acid or base medium.
- Process according to Claim 1, characterised in that in said stage c) said N-acylation is carried out in tetrahydrofuran, in the presence of NaHCO3 and at a temperature of between -10 and 10°C.
- Process for preparing the synthesis intermediate of formula (V), characterised in that it includes:a) Displacement of the Y group of a compound of formula (II) by the L-valine protected by trimethylsilyl (TMS) groups of formula (VIII):X means halogen or an -OSO2R group, where R is CF3, tolyl, methyl or F;Y means any leaving group capable of being displaced by the amine of the compound VIII; andR1 means hydrogen or a trimethylsilyl (TMS) group;where X and R1 have the meanings defined above, followed by:
- Process according to Claim 8, characterised in that stages a) and b) are carried out in a "one pot" reaction.
- Process according to Claims 8 and 9, characterised in that, where the silylating agent is 1,1,1,3,3,3-hexamethyldisilazane (HMDS), the "one pot" reaction includes:a) Prior formation of the p-toluenesulphonate of the L-valine in a polar solvent;b) "In situ" protection of the p-toluenesulphonate of the L-valine with one equivalent of 1,1,1,3,3,3-hexamethyldisilazane (HMDS) in the presence of an aprotic organic solvent under anhydrous conditions;c) Displacement of the Y group of the compound of formula (II) in said aprotic organic solvent at a temperature of between 25 and 150°C and in the presence of an organic base;d) Hydrolysis of the trimethylsilyl groups in an aqueous "work-up".
- Process according to Claim 10, characterised in that in said stage a) said polar solvent is alcohol or water.
- Process according to Claim 10, characterised
in that in said stage c) said displacement takes place at a temperature of between 40 and 100°C and in the presence of an organic base of the trialkylamine type Chosen from DTPEA, - Process according to Claims; 8 and 9, characterised in that, when the silylating agent is N,O-bis(trimethylsilyl)acetamide (BSA), the "one pot" reaction comprises:a) "In situ" protection of the carboxylic acid of the L-valine with one equivalent of N,O-Bis(trimethylsilyl)acetamide (BSA) in the presence of an aprotic organic solvent under anhydrous conditions;b) Displacement of the group Y of the compound of formula (II) at a temperature of between 25 and 150°C and in the presence of an organic base; andc) Hydrolysis of the trimethylsilyl group in an aqueous "work-up" to give the compound of formula (V).
- Process according to Claim 13, characterised in that in said stage a) said organic solvent is DMF.
- Process according to Claim 13, characterised in that in said stage b) said displacement occurs at a temperature of between 40 and 100°C and in the presence of an organic base of the trialkylamine type chosen from DIPEA.
- Process for preparing the synthesis intermediate of formula (VI), characterised in that, it consists in N-acylation, without protection of the carboxylic acid of the compound of formula (V), with valeroyl chloride:
- Process according to Claim 16, characterised in that said aprotic organic solvent is tetrahydrofuran (THF) and said inorganic base is NaHCO3.
- Process according to Claim 16, characterised in that said acylation is effected at a temperature of between -10 and 10°C.
- Process for preparing Valsartan, of formula I, characterised in that it consists in coupling of the intermediate of formula VI with the compound of formula VII:
in the presence of a solvent chosen from an aqueous or polar organic solvent, or a mixture of water and a water-miscible solvent, an organic or inorganic base able to form a salt with the tetrazole ring and in the presence of catalytic amounts of a palladium compound, at a temperature of between 25°C and 150°C. - Process according to Claim 19, characterised in that the reaction is carried out at a temperature of between 50°C and 100°C.
- Process according to Claim 19, characterised in that said coupling is carried out in homogeneous phase, if the palladium compound is soluble in the reaction medium, or in heterogeneous phase if the palladium compound is insoluble in the reaction medium.
- Process according to Claim 21, characterised in that if the palladium compound is soluble in the reaction medium it is chosen from Pd(PPh3)4, PdCl2 (PPh3)4, PdCl a (PPh 3 ) 2 , Pd (AcO)a.
- Process according to Claim 21, characterised in that if the palladium compound is insoluble in the reaction medium Pd/C is used and the coupling reaction is carried out in the presence of catalytic amounts of a ligand,
- Process according to claim 23, characterised in that said ligand is of the phosphine type, preferably triphenylphosphine or a phosphine soluble in water.
- Process according to claim 24, characterised in that said phosphine soluble in water is the trisodium salt of 3,3',3''-phosphinidinatris(benzensulphonate).
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EP1812411A2 (en) * | 2005-07-05 | 2007-08-01 | Teva Pharmaceutical Industries Ltd. | Process for preparing valsartan |
ITMI20051989A1 (en) * | 2005-10-20 | 2007-04-21 | Dipharma Spa | PROCEDIMERNTYO FOR THE PREPARATION OF ANAGOTENSIN ANTAGONISTIC COMPOUNDS II |
ES2288376B1 (en) * | 2005-10-20 | 2008-11-01 | Inke, S.A. | PROCEDURE FOR OBTAINING USEFUL INTERMEDIATES IN OBTAINING A PHARMACEUTICALLY ACTIVE COMPOUND. |
WO2007071750A1 (en) * | 2005-12-22 | 2007-06-28 | Enantia, S.L. | Intermediates and processes for the preparation of valsartan |
ES2300175B1 (en) * | 2006-02-14 | 2009-06-08 | Inke, S.A. | PROCEDURE FOR OBTAINING USEFUL INTERMEDIATES IN OBTAINING A PHARMACEUTICALLY ACTIVE COMPOUND. |
WO2008007391A2 (en) * | 2006-07-10 | 2008-01-17 | Manne Satyanarayana Reddy | An improved process for the preparation of valsartan |
DE602007000211D1 (en) * | 2007-06-07 | 2008-12-11 | Inke Sa | Process for obtaining a valsartan salt useful for obtaining valsartan |
EP2260018A2 (en) | 2008-04-07 | 2010-12-15 | Hetero Research Foundation | Process for preparation of valsartan intermediate |
KR101012135B1 (en) * | 2008-12-18 | 2011-02-07 | 주식회사 대희화학 | Process for preparing Valsartan methyl ester |
CN102702118B (en) * | 2012-06-11 | 2014-04-16 | 吉林三善恩科技开发有限公司 | Valsartan organic pharmaceutical co-crystal and preparation method thereof |
CN103804313B (en) * | 2014-01-27 | 2015-12-09 | 云南现代民族药工程技术研究中心 | A kind of succinct low-cost high-efficiency prepares the method for valsartan |
US9675585B1 (en) | 2016-03-24 | 2017-06-13 | Ezra Pharma | Extended release pharmaceutical formulations |
US9687475B1 (en) | 2016-03-24 | 2017-06-27 | Ezra Pharma Llc | Extended release pharmaceutical formulations with controlled impurity levels |
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EP1254899A2 (en) * | 1997-06-12 | 2002-11-06 | Schering Aktiengesellschaft | Piperazine derivatives and their use as anti-inflammatory agents |
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DE122007000050I1 (en) | 1990-02-19 | 2007-11-08 | Novartis Ag | acyl compounds |
DE4319040A1 (en) | 1992-10-23 | 1994-04-28 | Bayer Ag | Alkoxymethyl-substituted pyridone biphenyls |
DE4319041A1 (en) * | 1992-10-23 | 1994-04-28 | Bayer Ag | Trisubstituted biphenyls |
DE4313747A1 (en) * | 1993-04-27 | 1994-11-03 | Bayer Ag | Process for the preparation of substituted biphenyltetrazoles |
DE4320432A1 (en) * | 1993-06-21 | 1994-12-22 | Bayer Ag | Substituted mono- and bipyridylmethyl derivatives |
DE4407488A1 (en) | 1994-03-07 | 1995-09-14 | Bayer Ag | Use of bi:phenylyl-methyl- or phenyl-pyridyl-methyl- pyridone cpds. |
DK0782996T3 (en) | 1994-09-20 | 1999-09-20 | Wakunaga Seiyaku Kk | Process for the preparation of N-biphenylmethylthiadiazoline derivative or salt thereof and intermediate for the preparation of |
CA2434184A1 (en) * | 2001-01-19 | 2002-09-12 | Pharmacopeia, Inc. | Bisaryl derivatives having fsh receptor modulatory activity |
GB0121033D0 (en) * | 2001-08-30 | 2001-10-24 | Novartis Ag | Organic compounds |
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US7728021B2 (en) | 2010-06-01 |
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TW200539873A (en) | 2005-12-16 |
ES2251292A1 (en) | 2006-04-16 |
WO2005102987A1 (en) | 2005-11-03 |
DE602005008224D1 (en) | 2008-08-28 |
ES2251292B1 (en) | 2007-07-01 |
EP1747190A1 (en) | 2007-01-31 |
US20090221836A1 (en) | 2009-09-03 |
ATE401300T1 (en) | 2008-08-15 |
SI1747190T1 (en) | 2008-12-31 |
KR20060135959A (en) | 2006-12-29 |
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